A preferential inhibition by Zn2+ on platelet activating factor- and thrombin-induced serotonin secretion from washed rabbit platelets

Huo, Yinan; Ekholm, Janice E.; Hanahan, Donald J.

doi:10.1016/0003-9861(88)90515-2

Cited by 19 publications

(10 citation statements)

References 10 publications

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“…This hemostatic defect has also been found in humans during acute zinc deprivation and it has been attributed to an impaired platelet aggregation (Prasad 1979). By contrast, the serotonin release of rabbit and human platelets stimulated by platelet activating factor or thrombin was inhibited by in vitro incubation in the presence of micromolar concentrations of zinc (Huo et al 1988, Nunez et al 1989). However, long-term effects of zinc deficiency have not been extensively studied.…”

Section: Introductionmentioning

confidence: 93%

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Influence of a long-term zinc-deficient diet on rat platelet function and fatty acid composition

et al. 1995

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A reduced zinc intake is associated with numerous abnormalities and, in particular, with hemostasis dysfunction. In this report, we studied the effects of a long-term dietary zinc restriction on platelet function. Three groups of rats were analyzed: a zinc-deficient group (ZD) and two zinc-adequate fed groups, one pair-fed (PF) and one ad libitum fed (AL). We found that ZD diet (0.2 p.p.m.) impaired ADP-induced aggregation of washed platelet after 4 and 8 weeks of diet. Thrombin-induced aggregation was impaired in ZD rats and PF rats after 8 weeks. The thrombin-induced mobilization of radiolabeled arachidonate preincorporated into platelet phospholipids was followed as well as the subsequent formation of labeled cyclooxygenase and lipoxygenase products. Stimulated platelets of ZD rats exhibited a decreased production of cyclooxygenase and lipoxygenase products, particularly after 8 weeks of diet. Moreover, platelet thromboxane generation was decreased in the ZD group as studied using a radioimmunoassay after thrombin stimulation. In addition, we measured the total fatty acid compositions of platelet and plasma. As a whole, 20:5 (n - 3) and 22:5 (n - 3) fatty acids content were significantly increased in platelet lipids after 8 weeks. On the other hand, it is known that enrichment of these fatty acids through dietary studies, both in animal and human as well as in vitro incorporation in platelets, resulted in an inhibition of platelet function. Consequently, these changes in platelet membrane fatty acid composition may contribute to the impaired platelet aggregation observed in ZD rats.

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Section: Introductionmentioning

confidence: 93%

“…However, long-term effects of zinc deficiency have not been extensively studied. Data have been reported indicating some effects on lipid metabolism and membrane fluidity (Huo et al 1988). We have developed a model to study long-term zinc deficiency in rats.…”

Section: Introductionmentioning

confidence: 99%

Influence of a long-term zinc-deficient diet on rat platelet function and fatty acid composition

et al. 1995

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“…Binding to the PAF Receptor-Some reports indicated that zinc ions preferentially inhibit PAF binding and PAF-evoked cellular responses in rabbit and human platelets (20,21). We attempted to elucidate involvement in zinc binding of two histidines (His-188 and His-248) in TM V and VI domains, highly characteristic to the PAF receptors.…”

Section: Possible Involvement Of the Transmembrane Histidines In Zincmentioning

confidence: 99%

mentioning

confidence: 99%

“…We also generated a three-dimensional molecular model of the guinea pig PAF receptor TM regions, based on our mutagenesis studies and using bacteriorhodopsin as a reference protein. Thus, a pertinent explanation was obtained for reports that zinc ions preferentially inhibit specific PAF binding to its receptor in platelets (20,21 2 fragment were purchased from DuPont NEN. 1-O-Hexadecyl-2-O-acetyl-sn-glycero-3-phosphocholine (PAF C16), 1-O-octadecyl-2-Oacetyl-sn-glycero-3-phosphocholine (PAF C18), 1-O-hexadecyl-sn-glycero-3-phosphocholine (lyso-PAF C16) were obtained from Cascade Biochem (Reading, United Kingdom), and 1-O-hexadecyl-2-O-(methylcarbamyl)-sn-glycero-3-phosphocholine (methylcarbamyl-PAF C16) was from Cayman Chemical (Ann Arbor, MI).…”

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Alanine Exchanges of Polar Amino Acids in the Transmembrane Domains of a Platelet-activating Factor Receptor Generate Both Constitutively Active and Inactive Mutants

Ishii

Izumi

Tsukamoto

et al. 1997

Journal of Biological Chemistry

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To determine ligand-binding sites of a platelet-activating factor (PAF) receptor, alanine-scanning mutagenesis was carried out. All 23 polar amino acids in the putative 7-transmembrane (TM) domains of a guinea pig PAF receptor were individually replaced with alanine. The ligand-binding properties of mutant receptors were determined after transient expression in COS-7 cells. Mutants in TM II (N58A, D63A), TM III (N100A, T101A, S104A) and TM VII (D289A) displayed higher PAF-binding affinities than seen with the wild-type receptor. In contrast, mutants in TM V (H188A), TM VI (H248A, H249A, Q252A), and TM VII (Q276A, T278A) showed lower affinities. Representative mutants were then stably expressed in Chinese hamster ovary cells to observe PAF-induced cellular signals (arachidonate release, phosphatidylinositol hydrolysis, adenylyl cyclase inhibition). An N100A mutant with the highest affinity was constitutively active and was responsive to lyso-PAF, an inactive derivative of PAF. One nanomolar PAF induced no signals in low affinity mutants, an EC 50 value for the wild-type receptor. Three histidines (His-188, His-248, His-249) might form a binding pocket for the phosphate group of PAF, since zinc effectively inhibited ligand binding. Based on these results, a three-dimensional molecular model of PAF and its receptor was generated using bacteriorhodopsin as a reference protein.Platelet-activating factor (PAF), 1 is a potent phospholipid mediator with diverse physiological actions on a wide variety of cells and tissues. PAF is thought to play important roles in allergic disorders, inflammation, shock, and some diseases and also to have effects on the reproductive, cardiovascular, and central nervous systems (1-4). Despite the highly hydrophobic structure with a glycerophospholipid skeleton, PAF binds to a cell surface receptor, which was first cloned from a guinea pig lung cDNA library (5). The PAF receptor, with a seven-transmembrane (TM) topology like that of rhodopsin, belongs to a G protein-coupled receptor (GPCR) superfamily. PAF receptor homologs in four mammalian species (guinea pig, human, rat, and mouse) have been reported (6 -12). The PAF receptors couple with various second messenger systems including activation of phospholipase A 2 , C, and D; activation of mitogenactivated protein kinase, phosphatidylinositol 3-kinase, and tyrosine kinases; and inhibition of adenylyl cyclase, thus exerting pleiotropic effects (13-15).To date, a large body of information regarding ligand (agonist and antagonist)-binding characteristics of GPCRs represented by ␤-adrenergic receptors has been obtained (16), and this greatly contributes to effective clinical applications. Various PAF receptor antagonists have been developed as antiallergic and antiinflammatory drugs, but little is known of ligand-binding sites in the cloned PAF receptors. Most GPCR agonists are considered to bind to a hydrophobic core surrounded by seven-TM ␣-helices with electrostatic and hydrophobic force. We designed experiments using alanine-scanning muta...

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Zinc monoglycerolate: A slow-release source of zinc with anti-arthritic activity in rats

et al. 1990

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Zinc repletion by parental administration of zinc monoglycerolate (ZMG) or certain other lipophilic zinc complexes, suppressed the development of adjuvant-induced polyarthritis in rats. While ZMG was effective when given parenterally over various limited time schedules (immunosuppressant, therapeutic, singledose), it was not effective given orally. The complex showed no acute anti-inflammatory activity in the carrageenan paw oedema assay and little gastric-intestinal or other organ toxicity. When injected s.c. it caused very much less local irritation than most zinc salts. Being lubrous, ZMG could be applied as the dry powder for rubbing into the skin and by this route was found to have anti-arthritic activity. 65Zn was shown to be absorbed and excreted in the faeces (biliary excretion) after applying 65Zn-ZMG dermally to shaved dorsal skin of rats. ZMG showed consistent anti-arthritic activity in rats under conditions in which 2 gold drugs (aurothiomalate, Auranofin) exhibited variable effects, depending on the strain of rat. The role of zinc and its availability in chronic inflammation are discussed on the basis of these studies.

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A preferential inhibition by Zn2+ on platelet activating factor- and thrombin-induced serotonin secretion from washed rabbit platelets

Cited by 19 publications

References 10 publications

Influence of a long-term zinc-deficient diet on rat platelet function and fatty acid composition

Influence of a long-term zinc-deficient diet on rat platelet function and fatty acid composition

Alanine Exchanges of Polar Amino Acids in the Transmembrane Domains of a Platelet-activating Factor Receptor Generate Both Constitutively Active and Inactive Mutants

Zinc monoglycerolate: A slow-release source of zinc with anti-arthritic activity in rats

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